This program is dedicated to the translation of basic research findings into clinical trials of novel therapies for inflammatory bowel diseases (IBD) AND to using basic research methods to define the immune and genetic mechanisms underlying IBD in a variety of settings. This year's research accomplishments include:[unreadable] 1. Publishing results of a natural history study of the life-threatening enteropathy complicating common variable immuodeficiency (CVID) (Gastroenterology 131:748-756, 2006) identifying IL-12 and interferon-gamma as key effector cytokines in the absence of IL-23 or IL-17. Compared to CVID patients without gut disease, CVID patients with enteropathy had longer duration of immunodeficiency, had measurable malabsorption, and had peripheral blood naive T cell and NK cell deficiencies. These results are important because they demonstrate a human Th1 inflammatory bowel disease not associated with IL-23 (very different from Crohn's disease. e.g.). Furthermore these data became the basis for a new protocol using a novel drug to target IL-12 in the treatment of this condition particularly for inferiority compared to therapies targeting IL-12 in some way. [unreadable] 2. Publishing new findings showing that another Th1 cytokine, IL-23, plays a role in the inflammation of Crohn's disease (Inflam. Bowel. Dis. 12:9-15, 2006). This is important because it presents the possibility that other Th1 cytokines may play a significant role in ongoing inflammation this inflammation and that therapies targeting IL-23 specifically (e.g. the p19 subunit) should be tested for safety and effectiveness in Th1 diseases like Crohn's. [unreadable] 3. Reporting new findings that by targeting IL-13 in experimental ulcerative colitis treatment using interferon-beta (Clin. Immunol. 119: S33-34, 2006), we can induce clinical responses or remissions in a majority of patients; furthermore, more robust responses correlate with larger decreases in IL-13 production by lamin propria mononuclear cells. These findings have lead to discussions of expanded treatment protocols and development of new protocols using agents specifically targeting IL-13.[unreadable] 4. Publishing results of the NIH experience with gastrointestinal disease in Hermansky-Pudlak syndrome (Clin. Gastroenterol. Hepatol.,4: 73-80, 2006). Hermansky-Pudlak syndrome (HPS) is a model inherited disease for study of IBD etiology because it is caused by a defect in interacting proteins due to single gene mutations on different chromosomes. Patients with HPS have loss of pigment in the skin and eye (oculocutaneous albinism) with reduced vision, a platelet disorder leading to easy bleeding, and may develop pulmonary fibrosis. Patients with HPS also have a risk of IBD over ten-fold greater than the general population; the colitis may be granulomatous and we show that it is associated with only two of the known HPS gene defects. These findings are important because they summarize such data on the largest group of HPS subjects so studied, and the data suggest a genetic animal model to test susceptibility to IBD and measure individual function of the various parts of the mucosal immune system (from colonic biodiversity to molecular and cellular aspects of the innate and adaptive mucosal immune system) that may be affected by these defects. This retrospective study has lead to initiation of a prospective natural history study to define the cytokine and immune abnormalities associated with HPS inflammatory bowel disease. [unreadable]